The efficacy of repetitive transcranial magnetic stimulation for mild-to-moderate Alzheimer’s disease: a systematic review and meta-analysis of global cognitive outcomes

Objective To evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) on global cognitive function in patients with mild-to-moderate Alzheimer’s disease (AD), explore the moderating effects of different treatment parameters, and provide evidence-based guidance for clinical parameter optimization. Methods We systematically searched PubMed, Web of Science, the Cochrane Library, and Embase from inception to July 8, 2025. Randomized controlled trials (RCTs) comparing rTMS with sham rTMS in patients with mild-to-moderate AD were included. Cognitive function was assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or the Mini-Mental State Examination (MMSE). The systematic review protocol was registered with PROSPERO (CRD420261388581). Results Twenty RCTs involving 776 eligible patients were included. For studies reporting mean ± standard deviation, rTMS significantly improved ADAS-cog scores (SMD = − 0.51; 95% CI: −0.71 to − 0.31; Z = 4.95, p < 0.00001; I² = 0%) and MMSE scores (MD = 1.78; 95% CI: 1.15 to 2.41; Z = 5.56, p < 0.00001; I² = 0%). Subgroup analyses examined factors such as stimulation frequency (1 < f ≤ 10 Hz vs. f > 10 Hz), stimulation target (dorsolateral prefrontal cortex [DLPFC] vs. other brain regions), pulses per session (< 2000 vs. ≥2000), and intervention modality (rTMS alone vs. rTMS combined). The f > 10 Hz subgroup showed significant cognitive improvement, whereas the 1 < f ≤ 10 Hz subgroup did not. rTMS alone significantly improved both outcomes, while the combined intervention did not reach statistical significance. For studies reporting mean ± standard error, rTMS significantly improved both ADAS-cog and MMSE scores. Exploratory dose-response analysis revealed that weekly pulse count was positively associated with MMSE improvement immediately post-intervention (β = 0.0002, p = 0.0413) and at follow-up (β = 0.0003, p = 0.0247), and meta-regression further confirmed its suggestive effect at follow-up (β = 0.0001225, p = 0.028). Follow-up assessments demonstrated sustained cognitive gains. No significant publication bias was detected by Egger’s test for any outcome. Conclusion rTMS significantly improves global cognitive function in patients with mild-to-moderate AD, both immediately post-intervention and at follow-up. The cumulative weekly pulse count emerged as a promising parameter warranting prioritization in future dose-optimization trials, given its suggestive association with sustained cognitive gains.